rs1057519302

Variant names:

• chr2-8731515-C-CA
• rs1057519302
• NM_020738.4:c.4520dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001348729.2(KIDINS220):​c.4523dupT​(p.Leu1508PhefsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIDINS220 NM_001348729.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.06
• Publications: 1 publications found

Genes affected

KIDINS220 (HGNC:29508): (kinase D interacting substrate 220) This gene encodes a transmembrane protein that is preferentially expressed in the nervous system where it controls neuronal cell survival, differentiation into exons and dendrites, and synaptic plasticity. The encoded protein interacts with membrane receptors, cytosolic signaling components, and cytoskeletal proteins, serving as a scaffold that mediates crosstalk between the neurotrophin pathway and several other intracellular signaling pathways. Aberrant expression of this gene is associated with the onset of various neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease. Naturally occurring mutations in this gene are associated with a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

KIDINS220 Gene-Disease associations (from GenCC):

• spastic paraplegia, intellectual disability, nystagmus, and obesity

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• ventriculomegaly and arthrogryposis

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.15 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-8731515-C-CA is Pathogenic according to our data. Variant chr2-8731515-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 374910.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348729.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIDINS220	NM_020738.4	MANE Select	c.4520dupT	p.Leu1507PhefsTer4	frameshift	Exon 30 of 30	NP_065789.1
	KIDINS220	NM_001348729.2		c.4523dupT	p.Leu1508PhefsTer4	frameshift	Exon 30 of 30	NP_001335658.1
	KIDINS220	NM_001348731.2		c.4466dupT	p.Leu1489PhefsTer4	frameshift	Exon 29 of 29	NP_001335660.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIDINS220	ENST00000256707.8	TSL:1 MANE Select	c.4520dupT	p.Leu1507PhefsTer4	frameshift	Exon 30 of 30	ENSP00000256707.4
	KIDINS220	ENST00000488729.5	TSL:1	n.*4409dupT		non_coding_transcript_exon	Exon 29 of 29	ENSP00000417390.1
	KIDINS220	ENST00000488729.5	TSL:1	n.*4409dupT		3_prime_UTR	Exon 29 of 29	ENSP00000417390.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spastic paraplegia, intellectual disability, nystagmus, and obesity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519302; hg19: chr2-8871645;